Substituted imidazolyl-alkylthio-alkanoic acids

ABSTRACT

Angiotensin II receptor antagonists having the formula: ##STR1## which are useful in regulating hypertension and in the treatment of congestive heart failure, renal failure, and glaucoma, pharmaceutical compositions including these antagonists, and methods of using these compounds to produce angiotensin II receptor antagonism in mammals.

This application is a 371 of PCT/U.S. 93/06246 filed Jun. 30, 1993.

The present invention relates to new compounds which are angiotensin IIreceptor antagonists and are useful in regulating hypertension inducedor exacerbated by angiotensin II, and in the treatment of congestiveheart failure, renal failure, and glaucoma. This invention also relatesto pharmaceutical compositions containing these compounds and methodsfor using these compounds as antagonists of angiotensin II, asantihypertensive agents and as agents for treating congestive heartfailure, renal failure, and glaucoma.

BACKGROUND OF THE INVENTION

The class of peptide pressor hormone known as angiotensin is responsiblefor a vasopressor action that is implicated in the etiology ofhypertension in man. Inappropriate activity of the renin-angiotensinsystems appears to be a key element in essential hypertension,congestive heart failure and in some forms of renal disease. In additionto a direct action on arteries and arterioles, angiotensin II (AII),being one of the most potent endogenous vasoconstrictors known, exertsstimulation on the release of aldosterone from the adrenal cortex.Therefore, the renin-angiotensin system, by virtue of its participationin the control of renal sodium handling, plays an important role incardiovascular hemeostasis.

Interruption of the renin-angiotensin system with converting enzymeinhibitors, such as captopril, has proved to be clinically useful in thetreatment of hypertension and congestive heart failure (Abrams, W. B.,et al., (1984), Federation Proc., 43, 1314). The most direct approachtowards inhibition of the renin-angiotensin system would block theaction of AII at the receptor. Compelling evidence suggests that AIIalso contributes to renal vasoconstriction and sodium retention that ischaracteristic of a number of disorders such as heart failure, cirrhosisand complications of pregnancy (Hollenberg, N. K., (1984), J. Cardiovas.Pharmacol., 6, S176). In addition, recent animal studies suggest thatinhibition of the renin-angiotensin system may be beneficial in haltingor slowing the progression of chronic renal failure (Anderson, S., etal., (1985), J. Clin. Invest., 76, 612). Also, a recent patentapplication (South African Patent Application No. 87/01,653) claims thatAII antagonists are useful as agents for reducing and controllingelevated intraocular pressure, especially glaucoma, in mammals.

The compounds of this invention inhibit, block and antagonize the actionof the hormone AII, and are therefore useful in regulating andmoderating angiotensin induced hypertension, congestive heart failure,renal failure and other disorders attributed to the actions of AII. Whencompounds of this invention are administered to mammals, the elevatedblood pressure due to AII is reduced and other manifestations based onAII intercession are minimized and controlled. Compounds of thisinvention are also expected to exhibit diuretic activity.

Recognition of the importance of blocking and inhibiting the actions ofAII has stimulated other efforts to synthesize antagonists of AII. Thefollowing references have disclosed imidazole derivatives which aredescribed as having AII blocking activity and useful as hypotensiveagents.

Furukawa et al., U.S. Pat. No. 4,340,598 discloses imidazol-5-yl-aceticacids and imidazol-5-yl-propanoic acids. Specifically, the discloserincludes 1-benzyl-2-n-butyl-5-chloroimidazole-4-acetic acid and1-benzyl-2-phenyl-5-chloroimidazole-4-propanoic acid.

Furukawa, et al., U.S. Pat. No. 4,355,040 discloses substitutedimidazole-5-acetic acid derivatives. A compound specifically disclosedis 1-(2-chlorobenzyl)-2-n-butyl-4-chloroimidazole-5-acetic acid.

Carini et al., in European Patent Application Number 253,310 disclosecertain substituted imidazoles. An intermediate described in this patentis ethyl 3- 1-(4-nitrobenzyl)-2-butyl-4-chloroimidazol-5-yl!propenoate.

Carini et al., in European Patent Application Number 324,377 disclosesubstituted imidazoles and processes for their preparation. Thisapplication also relates to pharmaceutical compositions containing thesubstituted imidazoles alone and in conjunction with other drugs,particularly in conjunction with diuretics and non-steroidalantiinflammatory drugs.

DESCRIPTION OF THE INVENTION

The compounds of the present invention that are blockers of angiotensinII receptors are represented by the following Formula (I): ##STR2## inwhich: R¹ is adamantyl, phenyl, biphenyl, or naphthyl, with each phenyl,biphenyl, or naphthyl group being unsubstituted or substituted by one tothree substituents selected from Cl, Br, F, I, C₁ -C₆ alkyl, nitro,A--CO² R⁷, tetrazol-5-yl, C₁ -C₆ alkoxy, hydroxy, SC_(1-C) ₆ alkyl, SO₂NHR⁷, NHSO₂ R⁷, SO₃ H, CONR⁷ R⁷, CN, SO₂ C₁ -C₆ alkyl, NHSO₂ R⁷,PO(OR⁷)₂, NR⁷ R⁷, NR⁷ COH, NR⁷ COC₁ -C₆ alkyl, NR⁷ CON(R⁷)₂, NR⁷ COY, Y,or SO₂ Y;

R² is C₂ -C₁₀ alkyl, C₃ -C₁₀ alkenyl, C₃ -C₁₀ alkenyl, C₃ -C₆cycloalkyl, or (CH₂)₀₋₈ phenyl unsubstituted or substituted by one tothree substituents selected from C₁ -C₆ alkyl, nitro, Cl, Br, F, I,hydroxy, C₁ -C₆ alkoxy, NR⁷ R⁷, CO₂ R⁷, CN, CONR⁷ R⁷, Y, tetrazol-5-yl,NR⁷ COC₁ -C₆ alkyl, NR⁷ COY, SC₁ -C₆ alkyl, SO₂ Y, or SO₂ C₁ -C₆ alkyl;

X is a single bond, S, or O;

R³ is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl, COOR⁷ R⁷ CONR⁷ R⁷,NO₂, Y, CN, NR⁷ R⁷, or phenyl;

Y is C_(m) F_(2m+1) ;

A is --(CH₂)_(p) --, --CH═CH--, --O(CH₂)_(m) --, or --S(CH₂)_(m) ;

R⁴ is H, C₁ -C₆ alkyl, or --S(CH₂)₁₋₄ CO₂ R⁷ ;

t is 0 or 1;

R⁵ is --CHR⁶ (CH₂)_(q) CO₂ R⁷ or --(CH₂)_(n) R⁹ ;

R⁶ is hydrogen, CO₂ R⁷, C₁ -C₆ alkyl, or --(CH₂)_(n) R⁸ ;

each m independently is 1-3;

each n independently is 1-3;

each p independently is 0-4;

each q independently is 0-2;

each R⁷ independently is hydrogen or C₁ -C₆ alkyl;

R⁸ is phenyl, naphthyl, 2- or 3-thienyl, 2- or 3-thiazolyl, triazolyl,tetrazolyl, pyrazolyl, pyrrolyl, oxazolyl, or isoxazolyl, with each R⁸group being unsubstituted or substituted by C₁ -C₆ alkyl, C₁ -C₆ alkoxy,Cl, Br, F, I, NR⁷ R⁷, CONR⁷ R⁷, CO₂ R⁷, SO₃ H, SO₂ NHR⁷, OH, NO₂, Y, SO₂C₁ -C₆ alkyl, SO₂ Y, SC₁ -C₆ alkyl NR⁷ COH, NR⁷ COY, or NR⁷ COC₁ -C₆alkyl; and

R⁹ is phenyl, naphthyl, 2- or 3-thienyl, 2- or 3-furyl, 2-, 3-, or4-pyridyl, pyrimidyl, imidazolyl, thiazolyl, triazolyl, tetrazolyl,pyrazolyl, pyrrolyl, oxazolyl, or isoxazolyl, with each R⁹ group beingunsubstituted or substituted by C₁ -C₆ alkyl, C₁ -C₆ alkoxy, Cl, Br, F,I, NR⁷ R⁷, CO₂ R⁷, CONR⁷ R⁷, SO₃ H SO₂ NHR⁷, OH, NO₂, Y, SO₂ C₁ -C₆alkyl, SO₂ Y, SC₁ -C₆ alkyl, NR⁷ COH, NR⁷ COY, or NR⁷ COC₁ -C₆ alkyl; ora pharmaceutically acceptable salt thereof.

Preferred compounds of this invention are represented by Formula (I)when:

R¹ is phenyl or naphthyl, with each phenyl or naphthyl group beingunsubstituted or substituted by one to three substituents selected fromCl, Br, F, CF₃, NO₂, C₁ -C₆ alkyl, C₁ -C₆ alkoxy, hydroxy, A--CO₂ R⁷,CONR⁷ R⁷, or tetrazol-5-yl;

each p independently is 0-2;

X is a single bond or S;

R² is C₂ -C₈ alkyl;

R³ is hydrogen, Cl, F, CF₃, or NO₂ ;

R⁵ is --CHR⁶ (CH₂)_(q) CO₂ R⁷ in which R⁶ is hydrogen, CO₂ R⁷, C₁ -C₆alkyl, or (CH₂)_(n) R⁸, wherein R⁸ is phenyl, naphthyl, 2- or 3-thienyl,or 2- or 3-furyl, with each R⁸ group being unsubstituted or substitutedby C₁ -C₆ alkyl or C₁ -C₆ alkoxy; or --(CH₂)_(n) R⁹ in which R⁹ isphenyl or 2-, 3-, or 4-pyridyl with each R⁹ group being substituted byCO₂ R⁷, or R⁹ is imidazolyl; or a pharmaceutically acceptable saltthereof.

As used herein, the terms alkyl, alkenyl, alkoxy and alkynyl mean carbonchains which are branched or unbranched with the length of the chaindetermined by the descriptor preceding the term.

Particular compounds of the invention include, but are not limited to,the following:

S-(2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl)methyl!-D,L-2-thio-3-(2-thienyl)propenoicacid,

S-(2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl)methyl!thiogylcolicacid,

S-(2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl)methyl!thiolacticacid,

S-(2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl)methyl!-3-thiopropionicacid,

S-(2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl)methyl!mercaptosuccinicacid,

5-2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl!-4,6-dithianonane-1,9-dioic acid,

5-(2-n-butyl-1-{(4-carbomethoxyphenyl)methyl}-1H-imidazol-5-yl)methyl!-2-thio-3-(2-thienyl)propionic acid,

S-(2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl)methyl!-D-2-thio-3-phenylpropionicacid,

S-(2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl)methyl!-L-2-thio-3-phenylpropionicacid,

S-(2-n-butyl-1{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl)methyl!thiosalicylicacid,

S-(2-n-butyl-2-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl)methyl!-2-mercaptonicotinicacid,

4- (2-n-butyl-5-{(2-carboxyphenyl)thio!methyl}-1H-imidazol-5-yl)methyl!-1-naphthalenecarboxylicacid,

methyl 4- (2-n-butyl-5-{(2-carbomethoxyphenyl)-thio!methyl}-1H-imidazol-5-yl)methyl!-1-naphthalene-carboxylate,

S-(2-n-butyl-1-{(4-carboxyphenyl)methyl}-4-chloro-1H-imidazol-5-yl)methyl!thiosalicylicacid,

S-(2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl)methyl!-4-thiobenzoicacid,

S-(2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl)methyl!-3-thiobenzoicacid,

S-(2-n-butyl-1-{(4-carbomethoxyphenyl)methyl}-1H-imidazol-5-yl)methyl!-2-thioimidazole,

5 S-(2-n-butyl-1-{(4-carboxyphenyl)methyl}-4-nitro-1H-imidazol-5-yl)methyl!thiosalicylicacid,

S- (2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl!thiosalicylicacid,

S-(2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imdazole-5-yl!ethyl-thiosalicylicacid,

S- 2-(2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl)ethyl!thiosalicyclic acid,

S-(2-n-butyl-1-{(4-carboxyphenyl)methyl}-4-nitro-1H-imidazol-5-yl)methyl!mercaptoaceticacid, and

S-(2-n-butyl-1-{(4-carboxyphenyl)methyl}-4-nitro-1H-imidazol-5-yl)methyl!-L-2-thio-3-phenylpropionicacid; or a pharmaceutically acceptable salt thereof.

The most preferred compounds of this invention are:

S-(2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl)methyl!-2-thio-3-(2-thienyl)propenoic acid,

S-(2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl)methyl!thiosalicylicacid,

S-(2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl)methyl!-2-mercaptonicotinicacid,

4- (2-n-butyl-5-{(2-carboxyphenyl)thio!methyl}-1H-imidazol-5-yl)methyl!-1-naphthalenecarboxylicacid; or a pharmaceutically acceptable salt thereof.

The invention also relates to pharmaceutical compositions comprising apharmaceutical carrier and an effective amount of a compound of Formula(I).

Also included in the present invention are methods for antagonizingangiotensin II receptors which comprises administering to a subject inneed thereof an effective amount of a compound of Formula (I). Methodsof treating hypertension, congestive heart failure, glaucoma, and renalfailure by administering these compounds are also included in thisinvention.

The angiotensin II receptor antagonizing compounds are also of value inthe treatment of left ventricular hypertrophy regression, diabeticnephropathy, diabetic retinopathy, mascular degeneration, haemorrhagicstroke, primary and secondary prevention of infarction, prevention ofatheroma progression and the regression of atheroma, prevention ofrestinosis after angioplasty or bypass surgery, improving cognitivefunction, angina, and CNS disorders, such as anxiety.

The compounds of this invention are prepared by procedures describedherein and illustrated by the examples. Reagents, protecting groups andfunctionality on the imidazole and other fragments of the molecule mustbe consistent with the proposed chemical transformations. Steps in thesynthesis must be compatible with the functional groups and theprotecting groups on the imidazole and other parts of the molecule.

The following procedures are useful for the preparation of Formula (I)compounds particularly where R¹ is 4-carboxyphenyl, p is one, R² isn-propyl or n-butyl, X is S or a single bond, or R³ is hydrogen, Cl, F,NO₂, or CF₃. ##STR3##

Scheme I outlines the synthesis of Formula (I) compounds in which the2-position substituent is R² S. Benzylamines (1), unsubstituted orsubstituted by one to three Z substituents selected from halo, C₁ -C₆alkyl, SO₂ C₁ -C₆ alkyl, C₁ -C₆ alkoxy, CN, NO₂, CO₂ C₁ -C₄ alkyl, SC₁-C₆ alkyl, or C_(n) F_(2n+1), wherein n is 1-3, are alkylated with a C₁-C₆ alkyl chloroacetate, for example, methyl chloroacetate, in thepresence of a base, such as triethylamine, in a suitable solvent, suchas dimethylformamide. The resulting alkylaminoalkyl ester compounds (2)are N-formylated with formic acid in the presence of a suitable solvent,such as xylene, to give formula (3) compounds. Formula (4) compounds areformed by C-formylation of the carbon alpha to both the amino and theester groups of the formula (3) compounds in a reaction with an alkylformate, such as methyl formate, in the presence of an alkali metalhalide, such as sodium hydride, in a suitable solvent, such astetrahydrofuran. Reaction of this intermediate with acidic thiocyanate,preferably potassium thiocyanate, in an inert organic solvent, such asC₁₋₄ alkanol, produces formula (5) 1-R¹ CH₂ -2-mercapto-5-alkanoateester imidazoles. The free thio group of formula (5) compounds isreacted with a halo-R¹⁰ compound, wherein R¹⁰ is C₂₋₁₀ alkyl, C₃₋₁₀alkenyl, C₃₋₆ cycloalkyl, or an optionally substituted (CH₂)₀₋₈ phenyl,preferably propyl bromide, in the presence of a suitable base, such assodium carbonate, in an appropriate solvent, such as ethyl acetate, togive 1-R¹ CH₂ -2-R² S-5-alkanoate ester imidazoles (6). Thehydroxymethyl imidazoles of formula (7) are prepared from formula (6)compounds by reduction with an appropriate reagent, such as diisobutylaluminum hydride, in a suitable solvent, such as tetrahydrofuran, at atemperature of about -78° C. to about 25° C., preferably at about -10°C. The formula (8) chloromethyl compounds are prepared by reactingformula (7) hydroxymethyl compounds with a halogenating agent, such asrefluxing thionyl chloride. Reaction of formula (8) compounds with anappropriately substituted mercaptan, HSR^(5'), wherein R^(5') is-CHR^(6') (CH₂)_(q) CO₂ C₁ -C₆ alkyl, in which R^(6') is hydrogen, CO₂C₁₋₆ alkyl, C₁ -C₆ alkyl, or --(CH₂)_(n) R^(8') wherein R^(8') is asdefined for R⁸ except R^(8') is not substituted by CONR⁷ R⁷, CO₂ H, orOH, or wherein R^(5') is --(CH₂)_(n) R^(9') in which R^(9') is asdefined for R⁹ except R^(9') is not substituted by CONR⁷ R⁷, CO₂ H, orOH, in the presence of a base, such as triethylamine, in a suitablesolvent, such as dimethylformamide, at a temperature from about 30° C.to about 70° C., preferably from about 25° C. to about 60° C. Formula(I) compounds wherein R⁸ or R⁹ are substituted by CO₂ H, or R⁶ is CO₂ H,or R⁵ is --CHR⁶ (CH₂)_(q) CO₂ H are prepared from the corresponding CO₂C₁₋₆ alkyl compounds using aqueous base, such aqueous sodium carbonatesolution or aqueous sodium or potassium hydroxide solution, in asuitable organic solvent, such as methanol or ethanol.

Formula (I) compounds wherein R⁸ and R⁹ are substituted by CONR⁷ R⁷ areprepared from the Formula (I) compounds wherein R⁸ and R⁹ aresubstituted by CO₂ H. These carboxylic acid compounds are converted tothe corresponding acid halide derivatives using, for example, thionylchloride. The acid halide intermediate is then reacted with anappropriately substituted amine, HNR⁷ R⁷, to give the Formula (I)compounds wherein R⁸ or R⁹ are substituted by CONR⁷ R⁷.

Formula (I) compounds wherein R⁸ and R⁹ are substituted by OH areprepared from the Formula (I) compounds wherein R⁸ or R⁹ are substitutedby C₁ -C₄ alkoxy using an ether-cleaving reagent, such as borontribormide or hydrobromic acid. ##STR4##

Formula (I) compounds are also prepared by the procedures of Scheme II.The starting 2-R² X-imidazoles of formula (10) are known to the art (J.Org. Chem. 45:4038, 1980) or are synthesized by known procedures. Forexample, imidazole is converted to 2-n-butylimidazole by reactingimidazole with triethylorthoformate and p-toluenesulfonic acid to give1-diethoxyorthoamide imidazole and then treating with n-butyl lithium togive the 2-lithium derivative of the orthoamide and alkylating withn-butyl iodide in a suitable solvent, such as tetrahydrofuran.

The 1-R^(1') --(CH₂)₁₋₄ -group, wherein R^(1') is as defined for R¹except R^(1') is not substituted by A--CO₂ H, tetrazol-5-yl, hydroxy, orCONR⁷ R⁷, is incorporated onto the 2-R² X-imidazole of formula (10)byknown procedures, for example, by reaction with a R^(1') -(CH₂)₁₋₄halide, mesylate or acetate, such as 2-chlorobenzyl bromide or4-carbomethoxybenzyl bromide, in a suitable solvent, such asdimethylformamide, in the presence of a suitable acid acceptor, such assodium alkylate, potassium or sodium carbonate, or a metal hydride,preferably sodium hydride, at a reaction temperature of about 25° C. toabout 100° C., preferably at about 50° C. The resulting formula (11)imidazole is hydroxymethylated in the 5-position, for example, byreacting with formaldehyde in the presence of sodium acetate in aceticacid to provide the 1-R^(1') -(CH₂)₁₋₄ -2-R² X-5-hydroxymethylimidazoleintermediates of formula (12). Chloromethyl formula (13) compounds areprepared from formula (12) hydroxymethyl imidazoles in a reaction with ahalogenating agent, for example, refluxing thionyl chloride. Formula (I)compounds are prepared from the chloromethyl imidazoles by the methodsdescribed in Scheme I.

Alternatively, the 1-R^(1') -(CH₂)₁₋₄ -2-R² X-5-hydroxy-methylimidazoleintermediates of formula (12) are prepared by reacting an aimido ether,R² X--C(═NH)--O-alkyl, such as valeramidine methyl ether, or an amidine,such as valeramidine, with dihydroxyacetone in liquid ammonia underpressure to give 2-R² X-5-hydroxymethylimidazole. This intermediate isreacted with acetic anhydride to give 1-acetyl-5-acetoxymethyl-2-R²X-imidazole. The diacetate intermediate is N-alkylated, for example,using 2-chlorobenzyl triflate or 4-carbomethoxybenzyl triflate, and theresulting 1-R^(1') -(CH₂)₁₋₄ -2-R² X-5-acetoxymethyl-imidazole isde-protected using conventional acetate ester cleaving techniques, suchas treatment with aqueous base, for example aqueous sodium hydroxidesolution, to give the 1-R^(1') (CH₂)₁₋₄ -2-R² X-5-hydroxymethylimidazoleintermediate of formula (12). Formula (I) compounds are prepared fromthe hydroxy-methylimidazoles by the procedures detailed above.

Alternatively, Formula (I) compounds are prepared by the followingprocedure. Starting 2-R² X-imidazol-5-carboxaldehydes, prepared by theoxidation of the 2-R² X-5-hydroxymethylimidazoles describedhereinbefore, are reacted with an N-alkylating protecting reagent, suchas chloromethyl pivalate (POM-Cl), in the presence of a base, such aspotassium carbonate, in a suitable solvent, such as dimethylformamide,at a temperature of about 20° C. to about 50° C., preferably at about25° C., to give N-alkylation (e.g., POM-derivation) on the leasthindered nitrogen atom of the imidazole nucleus. The 1-R^(1') -(CH₂)₁₋₄-group is incorporated onto the imidazole by N-alkylation of the aboveprepared aldehyde with a halomethylbenzene compound, such as methyl4-bromomethylbenzoate, at a temperature of about 80° C. to about 125°C., preferably at about 100° C. The protecting group on the 3-nitrogenof the imidazole ring is removed by base hydrolysis, for example using abiphasic mixture of ethyl acetate and aqueous sodium carbonate, to give1-R^(1') CH₂ -2-R² X-imidazole-5-carboxaldehyde compounds. The Formula(I) compounds can be prepared from these 5-carboxaldehyde compounds bythe methods described above.

The 1-R^(1') --(CH₂)₁₋₄ -2-R² X-5-hydroxymethyl imidazole intermediates,wherein R³ is H, Cl, Br, or I, are prepared in the following manner. The2-R² X-5-hydroxyimidazole compounds, hereinbefore described, are treatedwith a N-halosuccinimide, such as bromo-, iodo- or chloro-succinimide,in a suitable solvent at a reaction temperature from about 30° C. toabout 80° C., preferably from about 40° C. to about. 60° C. The5-hydroxymethyl group is then oxidized to the corresponding5-carboxaldehyde derivative using a suitable oxidizing agent, such asmanganese dioxide, in an inert solvent, for example in methylenechloride, at a temperature of about 25° C. to about 40° C., preferablyat about 40° C. The --R^(1') --(CH₂) ₁₋₄ -group, wherein R¹ ' is asdefined previously, is incorporated onto the 2-R²X-4-halo-imidazol-5-carboxaldehydes by known proceedures, for example,by reaction with R^(1') --(CH₂)₁₋₄ -halide, such as methyl4-bromomethylnaphthalene-1-carboxylate or methyl 4-bromomethylbenzoate,in a suitable solvent, such as dimethylformamide, in the presence of asuitable base such as potassium carbonate at a temperature of about 40°C. to about 100° C., preferably at about 60C. The 4-halo group may beremoved catalytically, for example, by using palladium on carbon in thepresence of hydrogen and anhydrous potassium acetate in a suitablesolvent, such as in methanol, or, in the alternative, the halo group maybe retained on the imidiazole nucleus to prepare the Formula (I)compounds using the methods hereinbefore described.

Compounds wherein the R^(1') group is directly attached to the nitrogenof the imidazole ring are prepared following methods described in U.S.Pat. No. 4,194,049. For example, an appropriately substitutedbenzylamine is reacted with a R¹ '-nitrile, such as valeronitrile, inthe presence of a Lewis Acid, such as zinc chloride or aluminumchloride, in an inert organic solvent, such as tetrahydrofuran,methylene chloride, or toluene, at a temperature of about 25° C. toabout 150° C. The resulting amidine is converted to the 1-R^(1') -2-R²X-imidazol-5-carboxaldehyde derivative in a reaction with ahalomalonaldehyde, such as bromomalonaldehyde, in an appropriatesolvent, such as a C₁ -C₄ alkyl alcohol. The 5-hydroxymethylimidazole isprepared by reacting the 5-carboxaldehyde compound with a metal hydridereducing agent, such as sodium borohydride, in an organic solvent, suchas C₁ -C₄ alkyl alcohol. The Formula (I) compounds are prepared formthese alcohol intermediates using the methods described in Scheme I.

Formula (I) compounds wherein the alkylene bridge at the 5 position ofthe imidazole reing is defined as q equal to 0 are prepared as follows.The formula (10), Scheme II, imidazoles are reacted with a halogenatingagent, such as N-bromosuccinimide, in a suitable solvent, such as carbontetrachloride, at a temperature of about 40° C. to about 60° C.,preferably at about 60° C., to give the 2-R² X-4,5-dihaloimidazoleintermediate. This di-halo compound is converted to the 2-R²X-4-haloimidazole, compound such as 2-n-butyl-4-bromoimidazole, in areaction with sodium sulfite. Nitration of this intermediate using, forexample, nitric acid and sulfuric acid, gives 2-R²X-5-halo-4-nitroimidazoles. The 1-R^(1') -(CH₂)₁₋₄ -group_(p), whereinR¹ is as defined previously, is incorporated onto the 2-R²X-5-halo-4-nitroimidazoles by known procedures, for example, by reactionwith a R^(1') -(CH₂)₁₋₄ -halide, such as methyl 4-bromomethylbenzoate,in a suitable solvent, such as dimethylformaide, in the presence of asuitable base, such as potassium carbonate, at a temperature of about40° C. to about 100° C. The 5-halo group is displaced by HSR^(5'),wherein R^(5') is as defined for R⁵ except R^(5') is not substituted byCO₂ H, tetrazol-5-yl, hydroxy, or CONR⁷ R⁷, in the presence of a base,such as lithium diisopropylamine, in a suitable solvent, such astetrahydrofuran, at a temperature from about -78° C. to about 25° C. togive Formula (I) 1-R^(1') -(CH₂)₁₋₄ -2-R² X-4-NO₂ -5-SR^(5')-imidazoles. The 4-NO₂ compound may be converted the corresponding 4-Hcompound by reacting the nitro group with sodium hydrosulfide to givethe 4-NH₂ compound, which is subsequently de-aminated, for example, byusing sodium nitrate in the presence of a suitable solvent, such as amixture of hydrochloric acid, hypophosphorus acid and water, at atemperature from about -10° C. to about 10° C., preferably at 0° C.

Formula (I) compounds wherein the alkylene bridge at the 5-position ofthe imidazole ring is defined as q equal to 2 are prepared as follows.The 1-R^(1') -(CH₂)₁₋₄ -2-R² X-5-hydroxyethylimidazole intermediates areprepared by reacting an amidine, R² X--C(═NH)NH₂, such as valeramide,with methyl 3-formylacrylate to give 2-R²X-5-carbomethoxymethyl-imidazole compounds. The ester group is reducedto the corresponding alcohol using a suitable reagent, such as lithiumaluminum hydride, in a suitable solvent, such as tetrahydrofuran. TheFormula (I) compounds wherein q is 2 are prepared from the 2R²X-5-imidazol-ethanol compounds using the methods hereinbefore described.

Alternately, Formula (I) compounds wherein the alkylene bridge at the 5position of the imidazole ring is defined as q equal to 2 are preparedfrom the corresponding alkanoic esters, which are disclosed in U.S. Pat.No. 4,340,598. These ester imidazoles are reduced to the correspondingalcohols using a reducing agent such as lithium alumminum hydride, in aninert solvent, such as tetrahydrofuran. The Formula (I) compounds areprepared from these alcohol intermediates using the methods described inScheme I.

The compounds of the Formula (I) wherein R⁴ is --S(CH₂)₁₋₄ CO₂ R⁷ areconveniently prepared by forming the dithioacetal derivatives of1-R^(1') -(CH₂)₁₋₄ -2-R ² -X-imidazole-5-carboxaldehydes, preparedhereinbefore, utilizing the appropriate mercaptoalkanoic acids. Thereaction of the aldehyde with two equivalents of the mercaptoalkanoicacid is accomplished at about -10° C. to about 20° C., preferably atabout 0° C., under acidic conditions in an inert solvent. Examples ofsuch inert solvents include chlorinated hydrocarbons, such as, methylenechloride, chloroform and dichloroethane. The acidic conditions areproduced by mineral acids, such as hydrochloric acid and sulfuric acid,or Lewis acids, such as boron trifluoride etherate.

Compounds of Formula (I) in which the R¹ substituent or the R⁵ group issubstituted by hydroxy are formed from Formula (I) compounds in whichthe R¹ group is substituted by C₁ -C₄ alkoxy using an ether-cleavingreagent, such as boron tribromide or hydrobromic acid.

Compounds of Formula (I) in which the R¹ substituent or the R⁵ group issubstituted by carboxy are formed from Formula (I) compounds in whichthe R¹ group is substituted by CO₂ C₁ -C₄ alkyl using basic hydrolysis,such as aqueous sodium or potassium hydroxide in methanol or ethanol, orusing acidic hydrolysis, such as aqueous hydrochloric acid.

Compounds of Formula (I) in which the R¹ substituent or the R⁵ group issubstituted by a tetrazol-5-yl group are prepared from the correspondingcarboxy compounds. For example, Formula (I) acid compounds are reactedwith a halogenating agent, such as thionyl chloride, in a suitablesolvent, for example benzene, to give the corresponding acid halidecompounds. The acid halides are then converted to primary amidecompounds in a reaction with concentrated ammonia, to give Formula (I)compounds in which the R¹ substituent is substituted by CONH₂.Subsequent dehydration of the amides with oxalylchloride/dimethylformamide in acetonitrile/dimethylformamide yields thenitrile compounds, which are the immediate precursors to the Formula (I)tetrazole compounds. Tetrazole formation is accomplished by reacting thenitriles with azide, preferably aluminum azide prepared in situ by thereaction of sodium azide with. aluminum chloride, in a suitable solvent,for example tetrahydrofuran.

Compounds of Formula (I) in which the R¹ substituent or the R⁵ group issubstituted by CON(C₁ -C₆ alkyl)₂ are prepared from the correspondingcarboxy compounds. These carboxylic acid compounds are converted to thecorresponding acid halide derivatives using, for example, thionylchloride. The acid halide intermediate is then reacted with anappropriately substituted amine, HN (C₁ -C₆ alkyl)₂, to give the Formula(I) amide compounds.

Pharmaceutically acceptable acid addition salts of compounds of Formula(I) are formed with appropriate organic or inorganic acids by methodsknown in the art. For example, the base is reacted with a suitableinorganic or organic acid in an aqueous miscible solvent such as ethanolwith isolation of the salt by removing the solvent or in an aqueousimmiscible solvent when the acid is soluble therein, such as ethyl etheror chloroform, with the desired salt separating directly or isolated byremoving the solvent. Representative examples of suitable acids aremaleic, fumaric, benzoic, ascorbic, pamoic, succinic,bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic,propionic, tartaric, salicylic, citric, gluconic, aspartic, stearic,palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic,hydrochloric, hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric andnitric acids.

Pharmaceutically acceptable base addition salts of compounds of Formula(I) are prepared by known methods from organic and inorganic bases,including nontoxic alkali metal and alkaline earth bases, for example,calcium, lithium, sodium, and potassium hydroxide; ammonium hydroxide,and nontoxic organic bases, such as triethylamine, butylamine,piperazine, meglumine, choline, diethanolamine, and tromethamine.

Angiotensin II antagonist activity of the compounds of Formula (I) isassessed by in vitro and invivomethods. In vitro antagonist activity isdetermined by the ability of the compounds to compete with ¹²⁵I-angiotensin II for binding to vascular angiotensin II receptors and bytheir ability to antagonize the contractile response to angiotensin IIin the isolated rabbit aorta. In vivo activity is evaluated by theefficacy of the compounds to inhibit the pressor response to exogenousangiotensin II in conscious rats and to lower blood pressure in a ratmodel of renin dependent hypertension.

Binding

The radioligand binding assay is a modification of a method previouslydescribed in detail (Gunther et al., Circ. Res. 47:278, 1980). Aparticular fraction from rat mesenteric arteries is incubated in Trisbuffer with 80 pM of ¹²⁵ I-angiotensin II with or without angiotensin IIantagonists for 1 hour at 25° C. The incubation is terminated by rapid.filtration and receptor bound ¹²⁵ -angiotensin II trapped on the filteris quantitated with a gamma counter. The potency of angiotensin IIantagonists is expressed as the IC₅₀ which is the concentration ofantagonist needed to displace 50% of the total specifically boundangiotensin II. Exemplary of the IC₅₀ of compounds of the invention isabout 10.0 nM to about 3.0 μM.

Aorta

The ability of the compounds to antagonize angiotensin II inducedvasoconstriction is examined in the rabbit aorta. Ring segments are cutfrom the rabbit thoracic aorta and suspended in organ baths containingphysiological salt solution. The ring segments are mounted over metalsupports and attached to force displacement transducers which areconnected to a recorder. Cumulative concentration response curves toangiotensin II are performed in the absence of antagonist or following a30-minute incubation with antagonist. Antagonist disassociationconstants (K_(B)) are calculated by the dose ratio method using the meaneffective concentrations. Exemplary of the K_(B) of compounds of theinvention is about 4.0 nM to about 300 nM.

Inhibition of pressor response to angiotensin II in conscious rats

Rats are prepared with indwelling femoral arterial and venous cathetersand a stomach tube (Gellai et al., Kidney Int. 15:419, 1979). Two tothree days following surgery the rats are placed in a restrainer andblood pressure is continuously monitored from the arterial catheter witha pressure transducer and recorded on a polygraph. The change in meanarterial pressure in response to intravenous injections of 250 mg/kgangiotensin II is compared at various time points prior to and followingthe administration of the compounds intravenously or orally at doses of0.1 to 300 mg/kg. The dose of compound needed to produce 50% inhibitionof the control response to angiotensin II (IC₅₀) is used to estimate thepotency of the compounds. The IC₅₀ of S-(2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl)methyl!-thiosalicylic acid is about 0.50 mg/kg i.v.

Antihypertensive activity

The antihypertensive activity of the compounds is measured by theirability to reduce mean arterial pressure in conscious rats maderenin-dependent hypertensive by ligation of the left renal artery(Cangiano et al., J. Pharmacol. Exp. Ther. 208:310, 1979). Renal arteryligated rats are prepared with indwelling catheters as described above.Seven to eight days following renal artery ligation, the time at whichplasma renin levels are highest, the conscious rats are placed inrestrainers and mean arterial pressure is continuously recorded prior toand following the administration of the compounds intravenously ororally. The dose of compound needed to reduce mean arterial pressure by30 mm Hg (IC₃₀) is used as an estimate of potency.

The intraocular pressure lowering effects employed in this invention maybe measured by the procedure described by Watkins, et al., J. OcularPharmacol., 1 (2):161-168 (1985).

The compounds of Formula (I) are incorporated into convenient dosageforms, such as injectable preparations, or for orally active compounds,capsules or tablets. Solid or liquid pharmaceutical carriers areemployed. Solid carriers include starch, lactose, calcium sulfatedihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia,magnesium stearate, and stearic acid. Liquid carriers include syrup,peanut oil, olive oil, saline, and water. Similarly, the carrier ordiluent may include any prolonged release material, such as glycerylmonostearate or glyceryl distearate, alone or with a wax. The amount ofsolid carrier varies widely but, preferably, will be from about 25 mg toabout 1 g per dosage unit. When a liquid carrier is used, thepreparation will be in the form of a syrup, elixir, emulsion, softgelatin capsule, sterile injectable liquid, such as an ampoule, or anaqueous or nonaqueous liquid suspension.

For topical ophthalmolgic administration, the pharmaceuticalcompositions adapted include solutions, suspensions, ointments, andsolid inserts. Typical pharmaceutically acceptable carriers are, forexample, water, mixtures of water and water-miscible solvents such aslower alkanols or vegetable oils, and water soluble ophthalmologicallyacceptable non-toxic polymers, for example, cellulose derivatives suchas methyl cellulose. The pharmaceutical preparation may also containnon-toxic auxiliary substances such as emulsifying, preserving, wetting,and bodying agents, as for example, polyethylene glycols; antibacterialcomponents, such as quarternary ammonium compounds; bufferingingredients, such as alkali metal chloride; antioxidants, such as sodiummetabisulfite; and other conventional ingredients, such as sorbitanmonolaurate.

Additionally, suitable ophthalmic vehicles may be used as carrier mediafor the present purpose including conventional phosphate buffer vehiclesystems.

The pharmaceutical preparation may also be in the form of a solidinsert. For example, one may use a solid water soluble polymer as thecarrier for the medicament. Solid water insoluble inserts, such as thoseprepared from ethylene vinyl acetate copolymer, may also be utilized.

The pharmaceutical preparations are made following conventionaltechniques of a pharmaceutical chemist involving mixing, granulating,and compressing, when necessary, for tablet forms, or mixing, fillingand dissolving the ingredients, as appropriate, to give the desiredoral, parenteral, or topical products.

Doses of the compounds of Formula (I) in a pharmaceutical dosage unit asdescribed above will be an efficacious, nontoxic quantity selected fromthe range of 0.01-300 mg/kg of active compound, preferably 1-100 mg/kg.The selected dose is administered to a human patient in need ofangiotensin II receptor antagonism from 1-6 times daily, orally,rectally, topically, by injection, or continuously by infusion. Oraldosage units for human administration preferably contain from 1 to 500mg of active compound. Preferably, lower dosages are used for parenteraladministration. Oral administration, at higher dosages, however, alsocan be used when safe and convenient for the patient. Topicalformulations contain the active compound in an amount selected from0.0001 to 0.1 (w/v%), preferably from 0.0001 to 0.01. As a topicaldosage unit form, an amount of active compound from between 50 ng to0.05 mg, preferably 50 ng to 5 mg, is applied to the human eye.

The compounds of this invention may be co-administered with otherpharmaceutically active compounds, for example in combination,concurrently or sequentially. Conveniently the compounds of thisinvention and the other active compound or compounds are formulated in apharmaceutical composition. Examples of compounds which may be includedin pharmaceutical compositions with the compounds of Formula (I) arediuretics, particularly a thiazide diuretic, such ashydrochlorothiazide, or a loop diuretic, such as furosemide, a calciumchannel blocker, particularly dihydropyridine antagonists, such asnifedipine, β-adrenoceptor blockers, such as propranolol, renininhibitors, such as enalkinen, and angiotensin converting enzymeinhibitors, such as captopril or enalapril.

The AII receptor antagonist compounds of this invention can also beadministered in combination with other antihypertensives and/ordiuretics and/or angiotensin converting enzyme inhibitors and/or calciumchannel blockers. For example, the compounds of this invention can begiven in combination with such compounds as amiloride, atenolol,bendroflumethiazide, chlorothalidone, chlorothiazide, clonidine,cryptenamine acetates and cryptenamine tannates, deserpidine, diazoxide,guanethidene sulfate, hydralazine hydroahloride, metolazone, metoprololtartate, methyclothiazide, methyldopa, methyldopate hydrochloride,minoxidil, pargyline hydrochloride, polythiazide, prazosin, rauwolidaserpentina, rescinnaming, sylate, benzithiazide, quinethazone,ticynafan, triamterene, acetazolamide, aminophylline, cyclothiazide,ethacrynic acid, merethoxylline procaine, sodium ethacynate, delaprilhydrochloride, enalaprilat, fosinopril sodium, lisinopril, pentopril,quinapril hydrochloride, ramapril, teprotide, zofenopril calcium,diflusinal, diltizem, felodipine, nicardipine, niludipine, minodipine,nisoldipine, nitrenedipine, verapimil and the like, as well asadmixtures and combinations thereof. The AII receptor antagonistcompounds of this invention can also be administered in combination witha monoamine oxidase inhibitor, such as parnate.

To illustrate these combinations, one of the angiotensin II antagonistsof this invention effective clinically in the 2.5-250 milligrams per dayrange can be effectively combined at levels at the 0.5-250 milligramsper day range with the following compounds at the indicated per day doserange: hydrochlorothiazide (15-200 mg), chlorothiazide (125-2000 mg),ethacrynic acid (15-200 mg), amiloride (5-20 mg), furosemide (5-80 mg),propanolol (20-480 mg) timolol maleate (5-60 mg), 5 methyldopa (65-2000mg), felodipine (5-60 mg), nifedipine (5-60 mg), and nitrendipine (5-60mg). In addition triple drug combinations of hydrochlorothiazide (15-200mg) plus amiloride (5-20 mg) plus angiotnesin II antagonist of thisinvention (3-200 mg) or hydrochlorothiazide (15-200 mg) plus timololmaleate (5-60 mg) plus an angiotensin II antagonist of this invention(0.5-250 mg) of hydrochlorothiazide (15-200 mg) and nifedipine (5-60 mg)plus an angiotensin II antagonist of this invention (0.5-250 mg) areeffective combinations to control blood pressure in hypertensivepatients. Naturally, these dose ranges can be adjusted on a unit basisas necessary to permit divided daily dosage and, the dose will varydepending on the nature and severity of the disease, weight of patient,special diets and other factors.

No unacceptable toxicological effects are expected when compounds of theinvention are administered in accordance with the present invention.

The method of this invention of antagonizing angiotensin II receptors inmammals, including humans, comprises administering to a subject in needof such antagonism an effective amount of a compound of Formula (I). Themethod of this invention of treating hypertension, congestive heartfailure, glaucoma, and renal failure comprise administering a compoundof Formula (I) to a subject in need thereof an effective amount toproduce said activity.

Contemplated equivalents of Formula (I) compounds are compoundsotherwise corresponding thereto wherein substituents have been added toany of the unsubstituted positions of the Formula (I) compounds providedsuch compounds have the pharmaceutical utility of Formula (I) compounds.

The following examples illustrate preparation of compounds andpharmaceutical compositions of this invention. The examples are notintended to limit the scope of this invention as defined hereinabove andas claimed below.

EXAMPLE 1 S-(2-n-Butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-5-yl)methyl!-D,L-2-thio-3-(2-thienyl)-propionicAcid

(i) 2-Bromo-3-(2-thienyl)propionic Acid

Thienylalanine (17.1 g, 0.1 mol) was added to a solution of 40.2 g (0.34mol) of potassium bromide in 200 ml of 2.5N sulfuric acid. Solid sodiumnitrite (10.5 g, 0.15 mol) was added in portions over 45 minutes to thesolution which was held at 0°-4° C. The reaction mixture was stirred at0°-4° C. for 1 hour, and then stirred at 25° C. for 2 hours. The mixturewas extracted with ether and the ether extract was washed with water andbrine. The organic extract was dried and concentrated. The residue wasdissolved in 20 ml of ether and the solution diluted with petroleumether to the cloud point and then stored at -20° C. for 18 hours. Theinsolubles were removed by filtration and the solution concentrated togive 20.5 g (87%) of the product as an oil. The product was used in thenext step without further purification.

(ii) 2-Mercapto-3-(2-thienyl)propionic Acid

A solution of 7.05 g (0.03 mol) of the bromo acid in 45 ml ofdimethylformamide under argon was treated with 8.91 g (0.0315 mol) ofthe cesium salt of thiobenzoic acid (J. Org. Chem. 51, 3664). Themixture stirred for 18 hours at ambient temperature. The reactionmixture was diluted with 135 ml of ether and washed with water. Theether was dried and then concentrated to give 5.46 g (62%) of an oilwhose NMR was consistent with that expected for the 2-benzoylthioproduct. This oil (3.0 g) was dissolved in 41 ml of 1N ammonia andstirred for 18 hours under argon. After filtration, the pH was adjustedto 1 with 10% hydrochloric acid. The reaction mixture was extracted withether and the ether extract was washed with water, dried with sodiumsulfate, and concentrated to give the product as an oil.

(iii) 2-n-Butyl-5-hydroxymethylimidazole

A mixture of valeramidine methyl ether hydrochloride (250 g, 1.66 mol)and dihydroxyacetone (150 g, 0.83 mol) dissolved in liquid ammonia wasallowed to stand overnight at room temperature in a pressure vessel, andthen heated at 65° C. for 4 hours at 375 psi. The ammonia was allowed toevaporate, and the residue was dissolved in methanol (3L). The resultingslurry was refluxed with added acetonitrile (1L). The solution wasdecanted from the solid ammonium chloride while hot. This procedure wasrepeated, and the combined acetonitrile extracts were treated withcharcoal, filtered hot and the filtrate was concentrated in vacuum togive the dark oil, 2-n-butyl-5-hydroxy-methylimidazole (253 g, 1.63 mol,98%).

(iv) 2-n-Butyl-4-chloro-5-hydroxymethylimidazole

N-Chlorosuccinimide (54.68 g, 0.405 mol) was added in small portionsover 15 minutes to a stirred solution of2-n-butyl-5-hydroxymethylimidazole (50.00 g, 0.324 mol) in a mixture of580 ml of tetrahydrofuran and 500 ml of 2-methoxyethanol heated in anoil bath at 40°-50° C. under argon. After 2.5 h the mixture wasevaporated to dryness. The residue was suspended in 400 ml of water,stirred at 25° C. for 1 h. A tan solid was collected by filtration,washed with water and air dried to give 51.95 g of a mixture consistingof 2-butyl-4-chloro-5-hydroxymethylimidazole and 2-butyl-4,5-10dichloroimidazole. The dry powder was suspended in 150 ml of ether,stirred for 1 h at room temperature and then filtered to give 29.91 g(49%) of 2-n-butyl-4-chloro-5-hydroymethylimidazole; mp 150°-153° C.

(v) 2-n-Butyl-4-chloro-5-imidazolecarboxaldehyde

A stirred mixture of 2-n-butyl-4-chloro-5-hydroxymethylimidazole (15.00g, 0.0795 mol) and activated manganese dioxide (40.00 g) in 600 ml ofmethylene chloride was refluxed for 24 h using a water separator. Themixture was filtered hot through a Celite® pad. The Celite® pad waswashed several times with hot methylene chloride. The washings werecombined with the filtrate and concentrated in vacuo to give 12.81 g(86%) of the aldehyde as a white solid; mp 97°-98° C.

(vi) 2-n-Butyl-1- (4-carbomethoxybiphenyl-5-yl)methyl!-4-chloro-5-imidazolecarboxaldehyde

A mixture of 2-n-butyl-4-chloro-5-imidazole-carboxaldehyde (2.46 g,0.0132 mol) and anhydrous potassium carbonate (2.73 g, 0.0198 mol) in 25ml of dimethylformamide was stirred for 15 minutes at 25° C., then asolution of methyl 5-bromomethylphenyl-4-carboxylate (5.63 g, 0.0185mol) in 5 ml of dimethyl-formamide was added all at once (rinsed in with2×5 ml dimethylformamide). The mixture was heated in an oil bath at 105°C. for 20 minutes under argon, cooled, and then filtered. The filtercake was washed with ether and combined with the filtrate. The combinedorganics were washed with four 50 ml portions of water and then brine.The dried (sodium sulfate) filtrate was evaporated in vacuo to give asyrup (6.97 g). The crude product was flash chromatographed silica gel60, 230-400 mesh, 776 g, column 9.5 cm O.D., 9:1 cyclohexane/ethylacetate (2L) to 8:2 cyclohexane/ethyl acetate!to give 4.34 g(80%)ofproduct as a syrup.

(vii) 2-n-Butyl-1-(4-carbomethoxyphenyl)methyl!-5-imidazolecarboxaldehyde

A solution of 2-n-butyl-1-(2-carbomethoxyphenyl)-methyl!-4-chloro-5-imidazolecarboxaldehyde (3.05g, 0.00742 mol), anhydrous potassium acetate (0.66 g, 0.00742 mol) and10% palladium on carbon (0.73 g) in 100 ml of methanol was hydrogenatedat 35 psi for 45 minutes on a Parr shaker. The mixture was filteredthrough a Celite® pad. The Celite® pad was washed several times withmethanol and the combined filtrates evaporated in vacuo to a syrup. Theresidue was partitioned in an ether/water mixture. The aqueous phase wasadjusted to pH 8 with 5% aqueous sodium carbonate, extracted with ether,and the combined ether extracts were washed with water and brine. Thedried (sodium sulfate) solution was evaporated to a syrup (2.72 g)consisting mostly of product and some alcohol.

The syrup was dissolved in 50 ml of methylene chloride, 2.5 g ofactivated manganese dioxide was added and mixture was refluxed for 3 h.The mixture was filtered through a Celite® pad, the Celite® pad washedseveral times with methylene chloride and the combined filtratesevaporated in vacuo to give 2.64 g (95%) of product, as a syrup.

(viii) 2-n-Butyl-1- (4-carbomethoxyphenyl)methyl!-5-chloromethyl-1H-imidazole

Method 1

2-n-Butyl-1-(4-carbomethoxyphenyl)methyl!-1-H-imidazole-5-carboxaldehyde (6.07 g,0.202 mol) dissolved in 50 ml of methanol was treated portionwise with0.483 g (0.0128 mol) of sodium borohydride. After several minutes the pHof the mixture was brought to 7 with 10% hydrochloric acid. The mixturewas concentrated under vacuum and water was added. The resultingcrystals were collected by filtration, washed with water, and dried togive 5.90 g (97%) of the corresponding alcohol; mp 141°-143° C.

Method 2

2-n-Butyl-5-hydroxymethylimidazole (253 g) was treated with aceticanhydride (400 mL) at -15° C. and then was allowed to warm to ambienttemperature with stirring, and then stirred an additional 19 hours. Theacetic anhydride was evaporated at reduced pressure, the residue takenup in methylene chloride, and the organic phase was washed with 5%sodium bicarbonate solution and water. The extract was dried over sodiumsulfate and concentrated to give 323 g (83%) of1-acetyl-4-acetoxymethyl-2-n-butylimidazole.

This diacetate was N-alkylated by the following procedure. To a solutionof triflic anhydride (120 mL, 0.71 mol) in methylene chloride (200 mL)at -78° C. under argon was added a solution of diisopropyl ethylamine(128 mL, 0.73 mol) and 4-carbomethoxy alcohol (0.72 mol) in methylenechloride (350 mL) over a period of 20 minutes. After being stirred anadditional 20 minutes at -78° C., this solution is then treated with1-acetyl-4-acetoxymethyl-2-n-butylimidazole (146 g, 0.61 mol) dissolvedin methylene chloride (300 mL) over a 20 minute interval. The mixture isthen stirred at ambient temperature for 18 hours and the solvents areevaporated, The residual2-n-butyl-5-acetoxymethyl-1-(4-carbomethoxyphenyl)methyl-1H-imidazole isused without purification for the hydrolysis of the acetate group.

A crude2-n-butyl-5-acetoxymethyl-1-(4-carboxy-methoxy-phenyl)methyl-1H-imidazoleis stirred in methanol. After cooling, the methanol is removed in vacuo,methylene chloride is added, and the organic extract is washed withwater, dried and concentrated to give2-n-butyl-1-(4-carbomethoxyphenyl)-methyl-5-hydroxymethyl-1H-imidazole.

Thionyl chloride (7.5 ml) was added to 1.51 g (0.00499 mol) of thealcohol and the mixture was heated on a steam bath for 45 minutes.Concentration under vacuum gave a syrup which was treated with 30 ml ofether. The ether then removed under vacuum. Repetition of theether-evaporation cycle twice gave a solid which was taken up in 10 mlof methylene chloride and the solution added to ether to give 1.76 g(99%) of the chloromethyl imidazole hydrochloride; mp 151°-153° C.

(ix) S-(2-butyl-1-{(4-carbomethoxyphenyl)methyl}-1H-imidazol-5-yl)methyl!-D,L-2-thio-3-(2-thienyl) propionic Acid

A solution of 1.50 g (4.2 mmol) of the 5-chloro-methylimidazolehydrochloride, 0.99 g (5.2 mmol) of 2-mercapto-3-(2-thienyl)propionicacid, and 4 ml of triethylamine in 10 ml of dimethylformamide wasstirred at ambient temperature for 18 hours. The reaction mixture wasdiluted with water and extracted with ether. The aqueous layer wasextracted with ethyl acetate, the ethyl acetate and then organic extractwas dried over magnesium sulfate and concentrated. The residue waschromatographed (reverse phase C18 silica, 70% methanol-water) to give0.355 g of an oil which was dissolved in 5% sodium bicarbonate. Theaqueous layer was washed with ether and then the pH was adjusted to 4with dilute hydrochloric acid. The product was extracted into ethylacetate. The organic extract was dried over magnesium sulfate andconcentrated to give 0.265 g of the title compound isolated as an oil.

(x) S-(2-n-Butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl)methyl!-D,L-2-thio-3-(2-thienyl)propionic Acid

The mono-acid compound hydrolyzed by stirring with 0.9 g of potassiumhydroxide in a mixture of 4 ml of ethanol and 3 ml of water at 25° C.for 18 h. The hydrolysis mixture was evaporated to dryness, the residuewas dissolved in water and the solution was extracted with ether. Theorganic extract was made acidic and the resulting solid was collectedand washed with water to give a yellow solid; Anal. Caldc. for C₂₃ H₂₆N₂ O₄ S.1/2H₂ O: C, 59.08; H, 5.82; N, 6.00. Found: C, 59.02; H, 5.67;N, 5.92.

EXAMPLE 2 S-(2-n-Butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-5-yl)methyl!-D-2-thio-3-phenylpropionicAcid

Following the procedure of Example 1 replacing2-mercapto-3-(2-thienyl)-propionic acid with methylD-2-mercapto-3-phenylpropionic acid gave S- 2-Butyl-{1-{4-carboxyphenyl)methyl}-1H-imidazol-5-yl)!methyl!-D-2-thio-3-phenylpropionicacid hemihydrate; α!²⁵ (1, CH₃ OH) +2.5°, mp 80° C. (shrinks), 120°C.(turns glassy).

EXAMPLE 3 S-(2-n-Butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-5-yl)methyl!thioglycolicAcid

Following the procedure of Example 1 replacing2-mercapto-3-(2-thienyl)-propionic acid with methyl thioglycolate gaveS-(2-butyl-1-{(4-carboxyphenyl)-methyl}-1H-imidazol-5-yl)methyl!thioglycolicacid hemihydrate; softens at 125°-130° C.

EXAMPLE 4 S- (2-n-Butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl)methyl!-3-thiopronionic Acid

Following the procedure of Example 1 replacing2-mercapto-3-(2-thienyl)propionic acid with methyl 2-mercaptopropionategave S-(2-butyl-1-{(4-carboxy-phenyl)methyl}-1H-imidazol-5-yl)methyl!-3-thiopropionicacid; mp 70° C.

EXAMPLE 5 S-(2-n-Butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-5-yl)methyl!mercaptosuccinicAcid

Following the procedure of Example 1 replacing2-mercapto-3-(2-thienyl)propionic acid with dimethyl 2-mercaptosucinicacid gave S-(2-butyl-1-{(4-carboxy-phenyl)methyl}-1H-imidazol-5-yl)methyl!mercaptosuccinicacid; mp 140° C.

EXAMPLE 6 S-(2-n-Butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-5-yl)methyl!-L-2-thio-3-phenylpropionicAcid

Following the procedure of Example 1 replacing2-mercapto-3-(2-thienyl)propionic acid 1-phenylalanine S-(2-butyl-1-{(4-carboxyphenyl)methyl!-1H-imidazol-5-5-yl)methyl)-L-2-thio-3-phenylpropionicacid; α!₂₅ -1.3° (1%, CH₃ OH), mp 130° C.

EXAMPLE 7 S-(2-n-Butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-5-yl)methyl!thiosalicyclicAcid

Following the procedure of Example 1 replacing2-mercapto-3-(2-thienyl)propionic acid methyl 2-mercaptobenzoate S-(2-n-butyl-1-{(4-carboxyphenyl)-methyl}-2-butyl-1H-imidazol-5-yl)methyl!thiosalicyclicacid; shrinks at 90° C.

EXAMPLE 8 S-(2-n-Butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-5-yl)methyl!-4-thiobenzoicAcid

Following the procedure of Example 1 replacing2-mercapto-3-(2-thienyl)propionic acid methyl 4-mercaptobenzoate S-(2-n-butyl-1-{(4-carboxyphenyl)-methyl}-1H-imidazol-5-yl)methyl!-4-thiobenzoicacid; mp 213°-215° C.

EXAMPLE 9 S-(2-n-Butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-5-yl)methyl!-3-thiobenzoicAcid

Following the procedure of Example 1 replacing2-mercapto-3-(2-thienyl)propionic acid methyl 3-mercaptobenzoate S-(2-n-butyl-1-{(4-carboxyphenyl)-methyl}-1H-imidazol-5-yl)methyl!-3-thiobenzoicacid hydrate; mp 198°-200° C.

EXAMPLE 10 S-(2-n-Butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl)methyl!-2-mercaptonicotinicAcid

Following the procedure of Example 1 replacing2-mercapto-3-(2-thienyl)propionic acid methyl 2-mercaptonicotinate S-(2-n-butyl-1-{(4-carboxyphenyl)-methyl}-1H-imidazol-5-yl)methyl!-2-mercaptonicotinicacid; mp 155°-157° C.,

EXAMPLE 11 S-(2-n-Butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-5-yl)methyl!-2-thiomidazole

Following the procedure of Example 1 replacing2-mercapto-3-(2-thienyl)propionic acid 2-mercaptoimidazole S-(2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-5-yl)methyl!-2-thioimidazole;mp 142°-144° C.

EXAMPLE 12 S-(2-n-Butyl-1-{(4-carboxyphenyl)methyl}-4-chloro-1H-imidazol-5-yl)methyl!thiosalicyclicAcid

Following the procedure of Example 1 using 2-n-butyl-1-(4-carboxymethoxy)phenyl)methyl-4-chloro-5-chloromethylimidazole andmethyl 2-mercaptobenzoate gave S-(2-n-butyl-1-{(4-carbomethoxyphenyl)methyl-4-chloro-1H-imidazol-5-yl)methyl!thiosalicyclicacid; mp 166°-168° C.

EXAMPLE 13 5-2-n-Butyl-1-{(4-carboxyphenyl)methyl}-1-H-imidazol-5yl!-4,6-dithianonane-1,9-dioicAcid

A solution of 1.05 g (0.0035 mol) of 2-n-butyl-1-(4-carboxyphenyl)-methyl!-1H-imidazole-5-carboxaldehyde and 0.88 g(0.00734 mol) of methyl 3-mercaptopropionate in 50 ml of methylenechloride at 0° C. was treated with 5 0.992 g (0.007 mol) of borontrifluoride etherate. The reduced mixture was stirred for 30 minutes.The solution was then washed in turn with water, 5% sodium bicarbonate,and water. Drying and concentration gave an oil which on chromatography(silica, 80% ethyl acetate-hexane) gave two components, one of which wasconverted into the other on thin layer chromatography. This componentwas dissolved in ethyl acetate and stirred in the presence of silica for72 hours. Filtration and concentration under vacuum gave more of theproduct which was combined with the previous fraction to give 1.24 g(68%) of white crystals. The trimethyl ester of the title compound wasstirred for 18 hours in a solution of 0.766 g (0.0137 mol) of potassiumhydroxide in 60% aqueous ethanol. The mixture was diluted with water andextracted with ether. The aqueous layer was brought to pH 4 with dilutehydrochloric acid. This gave a solid from which the solution wasdecanted, and the solid was washed several times with water. Theresulting solid was triturated with acetonitrile and the resultinginsoluble product was purified by chromatography (reverse phase C18, 50%aqueous methanol) colorless crystals; Anal. Calcd. for C₂₂ H₂₈ N₂ O₆S₂.H₂ O: C, 53.00; H, 6.06; N, 5.62. Found: C, 53.23; H, 6.19; N, 5.22.

EXAMPLE 14 S-(2-n-Butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-5-yl)methyl!-mercaptoaceticAcid

(i) 4-Bromo-2-n-butylimidazole

A solution of 20 g (0.16 mol) of 2-n-butylimidazole in 1.2 L of carbontetrachloride was treated with 57.2 g (0.32 mol) of N-bromosuccinimdeand heated with good stirring at 60° for 18 h. Then an additional 10 gof N-bromosuccinimide was added and the heating continued for 4 hours.The solids were collected by filtration. Evaporation of the filtrategave 15 g of an oily solid which was mostly2-n-butyl-4,5-dibromoimidazole. Evaporation of the solution obtained bytrituration of the initial solids with methylene chloride andconcentration gave additional product which was chromatographed oversilica (20% ethyl acetate in hexane) to give, when combined with thefirst fraction, 34.2 g (76%) of dibromo product. A solution of 33.5 g(0.119 mol) of this product in 250 ml of n-propanol was refluxed for 18hours with a suspension of 100 g (0.794 mol) of sodium sulfite. Anadditional 50 g of sodium sulfite was added and the mixture refluxed anadditional 20 hours. The reaction mixture was concentrated under vacuum,800 ml of water was added, and then the product was extracted into etherat pH 8. The ether layer was washed with water and brine, dried oversodium sulfate, and concentrated to give 23 g of a solid. Chromatographyof the crude product (silica gel, 15-30% ethyl acetate-hexane) gave 7.51g (31%) of pure 2-n-butyl-4-bromoimidazole. On TLC (silica gel, 20%ethyl acetate in hexane) the dibromo imidazole had an R of =0.55 and wasvisible under short wavelength uv; the monobromo had an R of 0.25, wasnot visible under uv, but became visible when exposed to iodine vapor.

(ii) 5-Bromo-2-n-butyl-4-nitroimidazole

A solution of 7.51 g (37 mmol) of 4-bromo-2-n-butylimidazole in 50 ml ofanhydrous methanol was treated with total of 3.1 ml of 70% nitric acidto obtain the nitrate salt. The solvents were evaporated under vacuumand dried by successive additions of toluene followed by concentrationunder vacuum. The residue was taken to -70° C., treated with 30 ml ofconcentrated sulfuric acid, and slowly warmed to 70° C. The reactionmixture was held at 70° C., for 1 hour. The solution was poured into 800ml of an ice-water mixture to give a white solid which was collected byfiltration and washed with water to give 8.32 g (90.6%) of crystals,R_(f) 0.26 (silica, 20% ethyl acetate in hexane, weak iodine stain).

(iii) 5-Bromo-2-n-butyl-1-(4-carbomethoxyphenyl)-4-nitro-1H-imidazo!

Anhydrous powdered potassium carbonate (10.12 g, 73 mmol) was added to asolution of 8.26 g (33.3 mmol) of 5-bromo-2-n-butyl-4-nitroimidazole in60 ml of dry dimethylformamide. The reaction mixture was stirred at 60°C. for 45 minutes. A solution of 8.8 g (36.8 mmol) of methyl4-bromomethybenzoate in 15 ml of dry dimethylformamide was addeddropwise and the mixture stirred at 100°-105° C. for 1.5 hours. Thereaction mixture was poured into 700 ml of water and extracted withethyl acetate several times. The combined organic extracts were washedwith water and brine, and then dried over sodium sulfate. Evaporation ofthe solvent gave 14.4 g of a thick oil which on chromatography (600 mlsilica gel, 12.5-20% ethyl acetate in hexane) gave the title compoundR_(f) 0.51 (silica, 2:3 ethyl acetate-hexane).

(iv) S-(2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imdazole-5-yl!mercaptoaceticAcid

A solution of di-isopropylamine (0.7 ml, 0.005 mol) in 20 ml oftetrahydrofuran at -78° C. was treated with butyl lithium (2 ml, 2.5N,0.005 mol) and stirred for 0.5 h. Methyl thioglycolate (1 ml, 0.010 mol)was added and the mixture stirred for 0.25 h and warmed slightly to givea clear solution. A solution of 1.98 g (0.005 mol) of the abovebromonitro imidazole in 12 ml of tetrahydrofuran was added at -78° C.The mixture was allowed to warm to 25° over 0.75 h, and then heated atreflux for 0.5 h. The reaction mixture was filtered and the filter cakewashed with ethyl acetate. The combined filtrates were concentrated andthe residue chromatographed (silica gel, 20-30% ethyl acetate in hexane)to give the nitrosulfide.

A mixture of 0.88 g (2.09 mmol) of the nitrosulfide, 2 g (11.5 mmol) ofsodium hydrosulfite, 20 ml of water and 30 ml of ethanol was refluxedfor 18 h. The reaction mixture was poured into water, made basic withammonium hydroxide, and extracted with methylene chloride. The methylenechloride extract was washed with water, dried over sodium sulfate, andconcentrated to give the amino sulfide.

The amino sulfide (0.29 g, 0.74 mmol) was dissolved in a mixture of 1 mlof 12N hydrochloric acid, 1 ml of 50% hypophosphorous acid, and 2 ml ofwater. The reaction mixture was stirred at 0° C. for 10 minutes and thena solution of 0.10 g (1.5 mmol) of sodium nitrite in 2 ml of water wasadded. The mixture was stirred in the cold for 10 minutes. Extraction ofthe reaction mixture with methylene chloride followed by chromatography(20-50% ethyl acetate-hexane, silica gel) gave the deaminated sulfide.

A solution of 0.10 g (0.266 mmol) of the diester sulfide in 2 ml oftetrahydrofuran and 0.7 ml of methanol was treated with 0.58 ml (0.584mol) of 1N sodium hydroxide and stirred at 25° for 2.5 hours and then0.58 ml of 1N hydrochloric acid was added and the mixture concentratedto dryness. Repetition of the hydrolysis for 18 hours followed byneutralization and extraction with ethyl acetate gave the di-acid whichwas recrystallized from a mixture of ethyl acetate, ethanol, and hexane;mp 170°-172° C.

EXAMPLE 15 S-(2-n-Butyl-1-{(4-carboxyphenyl)methyl}-1H-imdazole-5-yl!thiosalicylicAcid

Following the procedure of Example 14 starting with5-bromo-2-n-butyl-1-(4-carbomethoxyphenyl)methyl!-4-nitro-1H-imidazoleand methyl 2-mercaptobenzoate gave S-(2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-5-yl)thiosalicylicacid; mp 260°-262° C. (ethyl acetate-hexane).

EXAMPLE 16 S--(2-n-butyl-1-{(4-carboxyphenyl!methyl}-1H-imidazol-5-yl)ethyl!thiosalicyclicAcid

(i) 2-n-Butylimidazole-4-acetic Acid. Ethyl Ester

Sodium hydride (2.82 g, 0,117 mol) was dissolved in 30 ml of absoluteethanol at 0° C. Valeramidine hydrochloride (16.71 g, 0.123 mol) wasadded to this solution, and after 15 minutes the solution was filteredand the collected solid was washed with 20 ml of ethanol and 50 ml ofbenzene. The combined filtrates were diluted with 750 ml of benzene, 15g (0.117 mol) of methyl 3-formylacrylate was added, and the mixture wasrefluxed for 18.5 h using a trap to remove water. The solvents wereremoved under vacuum and the residue slurried in ether. Evaporation ofthe ether solution gave the title compound as an oil.

(ii) 2(2-n-Butylimidazol-4-yl)ethanol

A solution of 2 g (9.5 mmol) of the above ethyl ester in 50 ml oftetrahydrofuran was added to a suspension of 0.76 g (20 mmol) of lithiumaluminum hydride in 50 ml of tetrahydrofuran. After stirring for 2hours, 3 ml of water was added dropwise, the solution was stirred for 18hours, and then 1 ml of 10% aqueous sodium hydroxide and 3 ml of waterwas added. After stirring for 1/2 hour, the mixture was filtered, thefilter cake was washed with tetrahydrofuran, and the combined filtrateswere concentrated under vacuum. Chromatography (silica gel, 5-10%methanol in ethyl acetate) gave the product as an amber oil.

(iii)5(2-Acetoxyethyl)-2-n-butyl-(4-carbomethoxyphenyl)methyl!-1H-imidazole

A solution of 1.37 g (8.1 mmol) of 2-(2-n-butylimidazol-4-yl)ethanol in20 ml of acetic anhydride was allowed to stand for 18 hours, refluxedfor 0.5 hours, and then stored for 72 hours. The solution wasconcentrated under vacuum, the residue was successively 3 timesdissolved in a mixture of toluene and hexane, and then it wasconcentrated to dryness. The resulting residue 1.69 g (85%) of1-acetyl-4-(2-acetoxyethyl)-2-butylimidazole.

A solution of trifluoromethanesulfonic anhydride (2.27 g, 8.04 mmol) in5 ml of methylene chloride at -78° C. was treated with a solution of1.34 g (8.04 mmol) of methyl 4-hydroxymethylbenzoate and 1.13 g (8.7mmol) of diisopropylethylamine in 10 ml of methylene chloride. Afterstirring for 5 hour, the above diacetyl imidazole derivative dissolvedin 10 ml of methylene chloride was added dropwise. The temperature wasallowed to rise to 25° cover an 18 hour period. The reaction mixture wasthen washed twice with 5% sodium bicarbonate, dried over sodium sulfate,and concentrated under vacuum. The residue was chromatographed (silicagel, 80-100% ethyl acetate-hexane) to give the title compound as an oil.

(iv) 2-n-Butyl-1-(4-carbomethoxyphenylmethyl)methyl!-5-(2-chloroethyl)-1H-imidiazole

A solution of the above diester (1.35 g, 3.77 mmol) in 2 ml of water and12 ml of methanol was stirred at ambient temperature for 2 h and thendiluted with ethyl acetate. After filtration the filtrate was washedwith water, dried over magnesium sulfate, and concentrated under vacuumto give 1.0 g (84%) of an oil which was 2-n-butyl-1-(4-carbomethoxyphenyl)methyl!-5-(2-hydroxyethyl)-1H-imidazole. This wasdissolved in 10 ml of thionyl chloride and refluxed for 2 h and thenvolatiles were removed under vacuum. The residue was treated with amixture of toluene and hexane and the solvents evaporated 3 times andhexane and the solvents evaporated 3 times in succession. The titlecompound was isolated as an oil.

(v) S- 2-(2-n-butyl-1{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl)ethyl!thiosalicylic Acid

Methyl thiosalicylate (0.323 g, 1.92 mmol) was added to a suspension of0.046 g (1.92 mmol) sodium hydride in 1 ml of dimethylformamide. Thesuspension was stirred until it became clear, then a solution of theabove chloride hydrochloride in 2 ml of dimethylformamide wets added andthe mixture stirred at ambient temperature for 18 h, followed by heatingat 90° for 5 hr. The mixture was poured into water, and extracted withethyl acetate. The organic layer was washed with water, dried, andconcentrated to give an oil which was chromatographed (silica gel, 80%ethyl acetate-hexane) to give the bis ester.

A solution of the bis ester (0.13 g, 0.66 mmol) in a mixture of 4 ml oftetrahydrofuran, 2 ml of methanol, and 1.5 ml (1.48 mmol) of 0.9861Nsodium hydroxide was stirred for 18 h. The mixture was neutralized with1.46 ml of 1N hydrochloric acid and chilled and the resulting crystalswere collected by filtration, washed with water, and dried to giveoff-white crystals; mp 293°-295° C.

EXAMPLE 17 4- (2-n-Butyl-5-{ (2-carboxyphenyl)thio!methyl}-1-imidazol-5-yl)methyl!-1-naphthalenecarboxylic Acid

(i) 2-n-Butyl-5-hydroxymethyl-4-iodoimidazole

N-iodosuccinimide (148.75 g, 0.661 mol) was added to a stirred solutionof 2-n-butyl-4-hydroxymethylimidazole (100.78 g, 0.652 mol) in 500 ml ofabsolute ethanol. After 20 minutes the solution was heated to 40°-45° C.for 45 minutes, diluted with 2.5 L of water, and chilled. Thecrystalline product which formed was collected by filtration, washedwith water, and dried to give 1.74.5 g (95%) of crystals; mp 166°-166.5°C.

(ii) 2-Butyl-4-iodoimidazole-5-carboxaldehyde

A stirred mixture of 174.1 g (0.62 mol) of2-n-butyl-5-hydroxymethyl-4-iodoimidazole and 360 g (4.14 mol) ofmanganese dioxide in 3 L of dichloromethane was refluxed for 24 hr usinga trap to remove water. The hot reaction mixture was filtered through aCelite® pad which was then washed with 4.5 L of boiling methylenechloride. The combined filtrates were concentrated to dryness. Theresidue was dissolved twice in 150 ml of methanol and each time thesolution was concentrated to dryness. The residue was dissolved in 130ml of methanol and chilled. After crystallization stopped, 700 ml ofwater was added slowly. The mixture was chilled, and the solid wascollected by filtration, washed with water and dried to give 145.2 g(84%) of product; mp 104°-105° C.

(iii) Methyl 4-(2-n-Butyl-5-formyl-4-iodo-1H-imidazol-5-yl)methyl!-1-napthalenecarboxylate

A suspension of 29.53 g (0.214 mol) of powdered potassium carbonate,60.00 g (0.214 mol) of 2-butyl-4-iodoimidazole-5-carboxaldehyde, and65.68 g (0.235 mol) of methyl 4-bromomethylnaphthalene-1-carboxylate (E.A. Dixon, A. Fischer, and F. P. Robinson, Can. J. Chem. 59, 2629 (1981))in 600 ml of dimethylformamide was stirred for 5 hours under argon at70° C. An additional 6.56 g (0.0235 mol) of the bromomethyl ester wasadded and the suspension was stirred an additional 15 hours at 70° C.The mixture was poured into water and the solid which separated wascollected by filtration, washed with water, and triturated several timeswith 250 ml of boiling methanol to give 86.8 g (85%) of a solid; mp177.5°-179° C.

(iv) Methyl4-(2-n-Buty-5-formyl-1H-imidazol-5-5-yl)methyl!-1-naphthalene carboxylate

A suspension of 40.0 g (83.0 mmol) of the iodo aldehyde, 9.07 g (92.4mmol) of potassium acetate, and 6.0 g of 10% palladium on carbon in 1.2liters of ethyl acetate was shaken under hydrogen in a Parr apparatusfor 2 hours. The solids were removed by filtration and an additional 8.0g of 10% palladium on carbon and 9.07 g (92.4 mmol) of potassium acetatewere added. After an additional 2 hours of shaking under hydrogen, thesolids were again removed by filtration and the solution concentrated toabout 1/3 volume. The ethyl acetate solution was washed with aqueoussodium carbonate, dried over magnesium sulfate, and concentrated undervacuum to give an oil which crystallized. Recrystallization from amethylene chloride-hexane mixture gave 25.77 g (87.6%) of colorlesscrystals; mp 95.5°-97° C.

(v) Methyl 4- (2-n-Butyl-5-{(2-carbomethoxyphenyl)-thio!methyl!-1-naphthalenecarboxylate

The title compound was prepared following the procedure of Example 1(viii-ix)replacing 2-n-butyl-1-(4-carbomethoxyphenyl)methyl-1H-imidazole-5-carboxaldehyde with methyl4- (2-n-butyl-5-formyl-1H-imidazol-5-yl)methyl!-1-naphthalenecarboxylate and replacing 2-mercapto-3-(2-thienyl)propenoic acid withmethyl 2-mercaptobenzoate; mp 130°-132° C.

(vi) 4- (2-n-Butyl-5-{(2-carboxyphenyl)thio!methyl}-H-imidazol-5-yl)methyl!-1-naphthalenecarboxylicAcid

The title compound was prepared following the procedure of Example (x);mp 272°-274° C.

EXAMPLE 18 S-(2-n-Butyl-1-{(4-carboxyphenyl)methyl}-1H-5-yl)methyl!thiolactic Acid

The title compound was prepared following the procedure of Example 1replacing 2-mercapto-3-(2-thienyl)propionic acid with ethyl thiolactate;mp 97° C. (D).

EXAMPLE 19 S-(2-n-Butyl-1-{(4-carboxyphenyl)methyl}-4-nitro-1H-imidazol-5-yl)methyl!mercaptoaceticAcid

The title compound was prepared as an amorphous solid following theprocedure of Example 14, except the nitro-reducing and deaminating stepsin subsection (iv) were not carried out; Anal. Calcd. for C₁₇ H₁₉ N₃ O₆S: C, 51.90; H, 4.86; N, 10.68. Found: C, 52.00; H, 5.16; N, 10.06.

EXAMPLE 20 S-(2-n-Butyl-1-{(4-carboxyphenyl)methyl}-4-nitro-1H-imidazol-5-yl)methyl!thiosalicylicAcid

The title compound was prepared following the procedure of Example 14,except the nitro-reducing and deaminating steps in subsection (iv) werenot carried out and methyl thioglycolate was replaced by methyl2-mercaptobenzoate; mp 246°-247° C.

EXAMPLE 21 S- (2-n-Butyl-1-{(4-carboxyphenyl)methyl}-4-nitro-1H-imidazol-5-yl)methyl!-L-2-thio-3-phenylpropionic Acid

The title compound was prepared following the procedure of Example 14,except the nitro-reducing and deaminating steps in subsection (iv) werenot carried out and methyl thioglycolate was replaced byL-phenylalanine; mp 105°-107° C.

EXAMPLE 22

An oral dosage form for administering orally active Formula (I)compounds is produced by screening, mixing and filling into hard gelatincapsules the ingredients in proportions, for example, as shown below.

    ______________________________________                                        Ingredients            Amounts                                                ______________________________________                                        S- (2-n-butyl-1-{(4-carboxy-                                                                         100 mg                                                 phenyl)methyl}-1H-imidazol-5-                                                 yl)methyl!thiosalicylic acid                                                  magnesium stearate     10 mg                                                  lactose                100 mg                                                 ______________________________________                                    

EXAMPLE 23

The sucrose calcium sulfate dihydrate and orally active Formula (I)compounds are mixed and granulated with a 10% gelatin solution. The wetgranules are screened, dried, mixed with the starch, talc and stearicacid, screened and compressed into a tablet.

    ______________________________________                                        Ingredients            Amounts                                                ______________________________________                                        S- (2-n-butyl-1-{(4-carboxyphenyl)-                                                                  75 mg                                                  methyl}-1H-imidazol-5-yl)methyl!-2-                                           thio-3-(2-thienyl)propenoic acid                                              calcium sulfate dihydrate                                                                            100 mg                                                 sucrose                15 mg                                                  starch                 8 mg                                                   talc                   4 mg                                                   stearic acid           2 mg                                                   ______________________________________                                    

EXAMPLE 24 S-(2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl)methyl!thiosalicylicacid, 50 mg, is dispersed in 25 mL of normal saline to prepare aninjectable preparation. EXAMPLE 25

A topical ophthalmological solution for administering Formula (I)compounds is produced by mixing under sterile conditions the ingredientsin proportions, for example, as shown below.

    ______________________________________                                                               Amounts                                                Ingredients            (mg/mL)                                                ______________________________________                                        S- (2-n-butyl-1-{(4-carboxyphenyl)-                                                                  1.0                                                    methyl}-1H-imidazol-5-yl)methyl!-2-                                           mercaptonicotinic acid                                                        dibasic sodium phosphate                                                                             10.4                                                   monobasic sodium phosphate                                                                           2.4                                                    chlorobutanol          5.0                                                    hydroxypropanol methylcellulose                                                                      5.0                                                    sterile water          q.s. ad 1.0 mL                                         1.0N sodium hydroxide  q.s. ad pH 7.4                                         ______________________________________                                    

It is to be understood that the invention is not limited to theembodiments illustrated hereabove and the right to the illustratedembodiments and all modifications coming within the scope of thefollowing claims is reserved.

What is claimed is:
 1. The compound which is:methyl 4- (2-n-butyl-5-{(2-carbomethoxyphenyl)-thio!methyl}-1H-imidazol-5-yl)methyl!-1-naphthalene-carboxylate;S- (2-n-butyl-1-{(4-carboxyphenyl)methyl}-4-chloro-1H-imidazol-5-yl)methyl!thiosalicylic acid; S-(2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl)methyl!-4-thiobenzoicacid; S-(2-n-butyl-1-{4-carboxyphenyl)methyl}-1H-imidazol-5-yl)methyl!-3-thiobenzoicacid; S-(2-n-butyl-1-{(4-carboxyphenyl)methyl}-4-nitro-1H-imidazol-5-yl)methyl!thiosalicylicacid; S-(2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imdazole-5-yl!thiosalicylicacid; or S-2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl)ethyl!thiosalicyclicacid; or a pharmaceutically acceptable salt thereof.
 2. The compoundwhich is S- (2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl)methyl!-thiosalicylic acid or a pharmaceutically acceptable saltthereof.
 3. The compound which is S-(2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl)methyl!-2-mercaptonicotinicacid or a pharmaceutically acceptable salt thereof.
 4. The compoundwhich is 4- (2-n-butyl-5-{(2-carboxyphenyl)thio!methyl}-1H-imidazol-5-yl)methyl!-1-naphthalenecarboxylicacid or a pharmaceutically acceptable salt thereof.
 5. The compoundwhich is S-(2-n-butyl-1-{(4-carbomethoxyphenyl)methyl}-1H-imidazol-5-yl)methyl!-2-thioimidazoleor a pharmaceutically acceptable salt thereof.